Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase

Abstract

There are described according to the invention, processes for making compounds of formula (XXVIII)3 (relative stereochemistry indicated), wherein P2 is as defined in the specification.

What is claimed is:  
     
       1. A process for preparation of a compound of formula (XXVIII) 3                      
       wherein P 2  is a protecting group, or a derivative in which the ring nitrogen is protected, or a salt thereof, which comprises the steps of: 
       (i) cyclizing a compound of formula (XLIV) 1                      
       wherein RX is selected from methyl iodide, benzyliodide and Me 2 SO 4 , and P 1 * represents CBZ, BOC or trifluoroacetyl; and 
       (ii) optionally protecting or deprotecting the product of step (i) and/or forming a salt thereof.  
     
     
       2. A process according to claim  1  wherein the compound of formula (XLIV) 1  is present as a single purified enantiomer of formula (XLIV) 2                      
       wherein RX and P 1*  are as defined in claim  1 . 
     
     
       3. A process according to claim  1  wherein P 1*  represents CBZ or BOC. 
     
     
       4. A process according to claim  1  wherein P 2  represents trifluoroacetyl. 
     
     
       5. A process for preparation of a compound of formula (I)                    
       (relative stereochemistry indicated) 
       wherein: 
       R 1  represents C 1-6 alkyl; C 2-6  alkenyl; aryl, aryl-C 1-4 alkyl, aryl-C 2-4 alkenyl, heteroaryl, heteroaryl-C 1-4  alkyl, or heteroaryl-C 2-4 alkenyl, or such a group in which the aryl or heteroaryl moiety is substituted by one or more C 1-4 alkyl, halo, tetrazolyl, trifluoromethyl-sulphonamide, NR 9 CO—C 1-8 alkyl, —(CH 2 ) m —NR 4 R 5 , —CN, —COOR 9 , —CONR 9 R 10 , —NO 2 , —SO 2 —C 1-6 alkyl —CF 3  or C 1-6  alkoxy groups; —(CH 2 ) n —NR 4 R 5 ; C 2-8 alkenyl-NR 4 R 5 ; —(CH 2 ) n CONR 4 R 5 ; —(CH 2 ) n NR 9 CO—C 1-6 alkyl; C 2-8 alkenyl-COOR 9 ; (CH 2 ) n COOR 9 ; and C 2-8 alkenyl CONR 4  R 5 ;  
       X represents                    
       (where carbonyl is bound to the ring nitrogen); 
       R 2  represents C 2-4 alkyl, C 2-4 alkenyl, C 1-3 alkoxy or C 1-3 alkylthio;  
       R 3  represents C 1-6 alkyl; —CH 2 (CF 2 ) 0-4 CF 3 ; aryl or heteroaryl, which aryl or heteroaryl are mono-ring, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C 1-4 alkyl, halo, —NR 7 R 8 , —SO 2 NR 7 R 8 , —CONR 7 R 8 , —C 1-6 alkyl ester, —CN, —CH 2 OH, —O—C 1-6 alkyl, —CF 3 , or nitro groups; aryl-C 1-4 alkyl, aryl-C 1-4 alkyl-NH— or aryl-C 2-4  alkenyl, or such groups wherein aryl is substituted by one or more C 1-4 alkyl or halo groups;  
       R 4  and R 5  independently represent hydrogen, C 1-4  alkyl, C 1-4 alkoxy, —(CH 2 ) 1-4 CONR 11 R 12 , —CO—C 1-4 alkyl or phenyl optionally substituted by one or more C 1-4 alkyl or halogen groups or R 4  and R 5  may be joined such that NR 4 R 5  represents a mono, bi- or tri-cyclic ring system containing 4-15 ring carbon atoms, wherein one or more rings may be optionally interrupted by one or more heteroatoms selected from O, N and S and wherein one or more ring carbon atoms may have carbonyl functionality;  
       or —(CH 2 ) n —NR 4 R 5  may represent a group of formula 1a:                    
       wherein R 6  is hydrogen or a carboxy C 1-6  alkyl ester, n 1  is 0-6 and a and b independently represent an integer 0-3 provided a+b is in the range 3-5;  
       R 7 , R 8 , R 9 , R 10 , R 11 , R 12  independently represent hydrogen or C 1-4  alkyl;  
       m represents an integer 0 to 8; n represents an integer 1 to 9;  
       or a salt or a solvate thereof which comprises the steps of:  
       (a) preparation of a compound of formula (XXVIII) 3                      
        wherein P 2  is a protecting group, or a derivative in which the ring nitrogen is protected, or a salt thereof, which comprises the steps of:  
       (i) cyclizing a compound of formula (XLIV) 1                      
        wherein RX and P 1*  are as defined in claim  1 ; and  
       (ii) optionally protecting or deprotecting the product of step (i) and/or forming a salt thereof; and  
       (b) reduction of a compound of formula (XXVIII) 3  or a derivative thereof in which one or both nitrogen atoms is protected, to give a compound of formula (XXIX) 2                      
        or a derivative thereof in which one or both nitrogen atoms is protected; and  
       (c) reacting a compound of formula (XXIX) 2 , or a derivative thereof in which one or both nitrogen atoms is protected, with a compound of formula (XXX)                    
        or a compound of formula (XXX) 2                      
        wherein R 2  is as defined above, to give a compound of formula (XL) 1                      
        wherein R 2  is as defined above; and  
       (d) cyclization of a compound of formula (XL) 1  to give a compound of formula (XXIII)                    
        wherein R 2  is as defined above; and  
       (e)  
       (i) sulphonation of a compound of formula (XXIII) or a derivative in which amine nitrogen is protected to give a compound of formula (II)                    
        wherein R 2  and R 3  are as defined above; and  
       (ii) if necessary, deprotection of the amine nitrogen, followed by condensation of a compound of formula (II) with a compound R 1 COOH, RCOY, R 1 OCOY or R 1 SO 2 Y, where Y is a reactive group to give a compound of formula (I); or  
       (f)  
       (i) condensation of a compound of formula (XXIII), or a derivative in which the amide nitrogen is protected, with a compound R 1 COOH, RCOY, R 1 OCOY or R 1 SO 2 Y, where Y is as defined above to give a compound of formula (III) 1                      
        wherein:  
       R 1 , R 2  and X are as defined above; and  
       (ii) if necessary deprotection of the amide nitrogen followed by sulphonation to give a compound of formula (I).  
     
     
       6. A process according to claim  4  wherein P 1*  represents CBZ and P 2  represents trifluoroacetyl.